Obesity is a major cause of insulin resistance and rising rates of obesity are responsible for the increasing prevalence of type 2 diabetes mellitus. In addition to its function in the uptake and storage of energy as triglyceride, the adipocyte is a complex endocrine cell that regulates feeding behavior and insulin action. However, the relationship between adiposity and diabetes is complex; for example, thiazolidinediones increase fat mass, yet improve insulin sensitivity. It is vital to define factors that regulate adipocyte function to understand how the adipocyte modulates such diverse processes. We have previously shown that two nuclear receptor corepressors, the silencing mediator of retinoid and thyroid hormone receptors (SMRT) and the nuclear receptor corepressor (NCoR), repress adipocyte gene expression during 3T3-L1 adipogenesis. In the proposed studies, we will test novel hypotheses to explain how SMRT and NCoR regulate adipocyte differentiation, adipocyte function, and insulin sensitivity. In Aim 1, we will test the hypothesis that SMRT and NCoR dictate the function of the differentiated adipocyte. In Aim 2, we will develop mouse embryonic fibroblasts deficient in SMRT to test the hypothesis that corepressors regulate adipogenesis and adipocyte apoptosis in primary cells. In Aim 3, we will define the roles of SMRT in adipocyte function and insulin sensitivity in vivo. By combining in vitro analysis of adipocyte cell lines, mouse embryonic fibroblasts, and isolated adipocytes, and by developing novel mouse models of corepressor deficiency to test our hypotheses in vivo, we will dissect the molecular mechanisms underlying corepressor action in the adipocyte. Understanding the roles of SMRT and NCoR in adipocyte biology is crucial if we are to design novel approaches to the treatment of obesity and diabetes. PUBLIC HEALTH RELEVANCE: Obesity is a risk factor for the development of type 2 diabetes mellitus, and diabetes is a major cause or blindness, kidney disease, amputation, and death. The goal of these studies is to test the hypothesis that two proteins, SMRT and NCoR, are important in fat cell (adipocyte) function and the ability of the body to respond to insulin. These results will be helpful in the design of new medications to treat patients with diabetes